The present invention relates to novel polypeptide sequences, polynucleotides encoding same and antibodies generated thereagainst which can be used to diagnose and treat cancer and skeletal disorders, such as osteoporosis.
Organization and differentiation of the embryo into distinct tissues requires adhesive mechanisms that promote and maintain physical segregation and association. The differentiation of mesenchymal stem cells to skeletal tissues occurs in response to microenvironmental signals evoked by cell adhesion molecules and affinities that control responses to hormones and growth factors (Ferguson et al., 1998; Olsen et al., 2000; Tepass et al., 2002; Triffitt et al., 1998). The differentiation of bone marrow cells that are maintained in a specific microenvironment is controlled by cell-cell and cell-matrix interactions mediated by selectins and integrins, which switch on intracellular signaling pathways regulating cell function (Jaiswal et al., 2000; Patel et al., 2002; Shur et al., 2001).
In a mammal, bone shape is maintained by continuous remodeling or sculpturing of its surface through two major processes, including bone formation and bone resorption, which are regulated by various soluble factors, systemic hormones, cell adhesion molecules, and focal mechanical stress (Arai et al., 2003; Goltzman, 2002). Osteoblasts, the cells from which bone develops, play a central role in bone formation by synthesizing and mineralizing bone matrices. Osteoblasts and their progenitors (bone marrow stromal cells) also function in the control of bone resorption by acquiring a supportive activity for osteoclast differentiation (Arai et al., 2003). An osteoclast, or an osteophage, is a large, multinucleate cell found in growing bone that resorbs bony tissue, as in the formation of canals and cavities or in a fracture that is healing. Osteoclastogenesis is the process of formation and development of osteoclasts, whereas osteogenesis is the process of formation and development of bony tissue from osteoblasts.
The differentiation and function of bone marrow and skeletal cells underlying bone remodeling processes is primarily regulated by estrogen. The effects of this hormone are integrated into multiple regulatory pathways that coordinate cell growth and proliferation (Brigstock, 2003; Manolagas et al., 2002; Spelsberg et al., 1999). Estrogen deficiency in vivo, e.g., at the postmenopausal period or after ovariectomy, stimulates skeletal destruction by increased osteoclastogenesis and decreased osteogenesis. (Benayahu et al., 2000; Ishihara et al., 1999; Liu et al., 2000; Watts, 2000).
Estrogens act to weaken the adhesive property of osteoclasts by inhibiting the activity of β-integrin adhesion molecules and thereby changing the cells' mode of interaction with the bone microenvironment (Duong et al., 1998; Moggs et al., 2003; Saintier et al., 2004). However, the precise mechanism whereby estrogen stimulates osteoblasts and bone formation is still unknown. Estrogenic regulation of transcriptional and translational events is mediated through cell surface molecules that activate signal transduction pathways in osteoblasts (Monroe et al., 2003, Plotkin et al., 2002, Rickard et al., 1999). The signals are translated to anti-apoptotic events (Manolagas et al., 2002) and modulate intracellular calcium levels, IP3, and cAMP through gap junctions (Massas et al., 1998; Lieberherr et al., 1993). These estrogenic effects on stromal and osteoblastic cells are mediated through specific cell surface proteins that interact with the microenvironment.
Some approaches for the treatment of bone disorders such as osteoporosis include, for example, estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators. Other approaches include peptides from the parathyroid hormone family, strontium ranelate, and growth hormone and insulin-like growth response [see, for example, Reginster et al. “Promising New Agents in Osteoporosis” Drugs R & D 1999, 3, 195-201]. Unfortunately, these therapeutic agents still have significant shortcomings.
The variety of different approaches represented by the therapeutic agents currently available or under study evidence the variety of biological factors influencing the competing processes of bone production and resorption.
Although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop new therapeutic agents which have an improved therapeutic efficacy, which may be given to patients who cannot well tolerate or do not respond to existing therapies, and/or which may be used in conjunction with other therapies.